What are the risks of taking allopurinol?

Risks of Allopurinol

Allopurinol carries a rare but potentially life-threatening risk of severe hypersensitivity reactions, with mortality rates of 20-25%, alongside more common risks of hepatotoxicity, bone marrow suppression, and increased malignancy risk when used with certain immunosuppressants. 1

Severe Hypersensitivity Reactions

Allopurinol Hypersensitivity Syndrome (AHS)

• The most serious risk is AHS, occurring in approximately 1 in 1,000 patients in the USA, characterized by erythematous desquamating rash, fever, hepatitis, eosinophilia, and progressive renal failure with a 20-25% mortality rate. 1

• The syndrome includes Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis, along with systemic vasculitis and major end-organ disease. 1

• The highest risk period is within the first few months of therapy. 1

• The FDA mandates that allopurinol must be discontinued at the first appearance of skin rash or other signs of allergic reaction, as rash may progress to severe hypersensitivity reactions, generalized vasculitis, irreversible hepatotoxicity, and death. 2

Genetic and Ethnic Risk Factors

• Asian and Black patients face substantially higher risk: hospitalization rate ratios for Stevens-Johnson syndrome/toxic epidermal necrolysis are 11.9 for Asian patients, 5.0 for Black patients, and 1.0 for White patients. 1

• The HLA-B*5801 allele confers hazard ratios of several hundred in high-risk populations, with allele frequencies of 7.4% in Asian Americans, 4% in Black Americans, and 1% in White Americans. 1

• HLA-B*5801 testing should be performed before initiating allopurinol in Korean patients with stage 3 or worse chronic kidney disease, or in Han Chinese or Thai patients regardless of renal function. 1, 3

• If HLA-B*5801 is positive in these high-risk populations, an alternative to allopurinol must be prescribed. 1

Hepatotoxicity

• Reversible clinical hepatotoxicity occurs in some patients, with asymptomatic rises in serum alkaline phosphatase or transaminases observed. 2

• If anorexia, weight loss, or pruritus develop, liver function evaluation is mandatory. 2

• In patients with pre-existing liver disease, periodic liver function tests are required during early therapy stages. 2

• Hepatitis with eosinophilia was documented in 69% of hospitalized patients with allopurinol adverse reactions. 4

Hematologic Toxicity

• Significant bone marrow suppression occurred in documented cases when allopurinol was used with purine analogues. 1

• Leukocytosis was present in 62% and eosinophilia in 54% of hospitalized patients with allopurinol adverse reactions. 4

• Allopurinol is contraindicated with cyclophosphamide and other cytotoxic agents due to increased bone marrow suppression. 3

Drug Interaction Risks

• When co-prescribed with mercaptopurine or azathioprine, these drugs require dose reduction to one-third to one-fourth of usual doses to prevent severe toxicity. 2, 3

• A 65-75% dose reduction of purine-based chemotherapeutic agents is necessary when used concomitantly with allopurinol due to reduced clearance. 3

• Monitoring for purine analogue metabolites is encouraged when co-prescribed with allopurinol, particularly given persistent risks of hepatotoxicity and myelosuppression. 1

Renal Function-Related Risks

• Concurrent thiazide use and renal impairment are established risk factors for AHS. 1

• The occurrence of hypersensitivity reactions is increased in patients with decreased renal function receiving thiazides and allopurinol concurrently, requiring close observation. 2

• Renal impairment was present in 54% of hospitalized patients with allopurinol adverse reactions. 4

• Oxypurinol (allopurinol's metabolite) clearance is directly proportional to creatinine clearance, leading to elevated steady-state concentrations in renal insufficiency that increase toxicity risk. 5

Malignancy Risk (with Purine Analogues)

• When allopurinol is used to optimize purine analogue therapy, patients face the underlying malignancy risks of purine analogues, including lymphoma (pooled incident rate ratio 2.23) and non-melanoma skin cancer (relative risk 1.88). 1

Other Adverse Effects

• Drowsiness may occur, requiring caution when engaging in activities requiring alertness. 2

• Minor skin reactions occurred in 4.5% of patients in one study, though these were not serious. 6

• Acute pancreatitis has been documented when allopurinol is used with purine analogues. 1

Risk Mitigation Strategies

• Start with no more than 100 mg daily, or 50 mg daily in stage 4 or worse chronic kidney disease, to minimize hypersensitivity risk. 1, 3

• Dose reduction of at least 50% is required in patients with renal insufficiency. 3

• Gradual titration from low starting doses minimizes acute gout attack risk. 3

• Allopurinol should only be prescribed when truly indicated, given the severity of potential adverse reactions. 4